Somatic mutations increase hepatic clonal fitness and regeneration in chronic liver disease
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ABSTRACT:
PROVIDER: EGAS00001003496 | EGA |
REPOSITORIES: EGA
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Project description:Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness, however, it is uncertain if these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP activation. In summary, PKD1 mutations in cirrhotic livers exert adaptive functionality without increasing transformation risk.
2024-05-15 | GSE264521 | GEO
Project description:Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness, however, it is uncertain if these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP activation. In summary, PKD1 mutations in cirrhotic livers exert adaptive functionality without increasing transformation risk.
2024-05-15 | GSE264520 | GEO
Project description:The transcriptional coactivator Yap promotes proliferation and inhibits apoptosis, suggesting that Yap functions as an oncogene. Most oncogenes, however, require a combination of at least two signals to promote proliferation. Here we present evidence that Yap activation is insufficient to promote growth in the otherwise normal tissue. Using a mosaic mouse model, we demonstrate that Yap overexpression in a fraction of hepatocytes does not lead to their clonal expansion, as proliferation is counterbalanced by increased apoptosis. To shift the activity of Yap towards growth, a second signal provided by tissue damage or inflammation is required. In response to liver injury, Yap drives clonal expansion, suppresses hepatocyte differentiation and promotes a progenitor phenotype. These results suggest that Yap activation is insufficient to promote growth in the absence of a second signal thus coordinating tissue homeostasis and repair. Totally sixteen samples
2015-02-07 | E-GEOD-65207 | biostudies-arrayexpress
Project description:Histone lysine methyltransferases KMT2C and KMT2D are among the most commonly mutated genes in the highly metastatic TNBC subtype of breast cancer. However, it is not known if mutations of either of these genes similarly effect epigenomic and transcriptomic landscape or if a specific downstream target might influence metastases. Here, we generated heterogenous Kmt2c or Kmt2d KO murine TNBC cell lines side-by-side and performed in vivo metastases assay in syngeneic immunocompetent mice. Deficiency for either Kmt2c or Kmt2d, both, induced brain metastases from formerly non-metastatic cells. scRNAseq showed activation of pro-inflammatory pathways but conversely also increase of immune checkpoint blocking genes. Interestingly, histone mass spectrometry revealed changes of H3K27 but not the main substrate H3K4. However, ChIPseq for both, H3K4 and H3K27 modifications showed significant changes compared to wildtype cells. Strikingly, genome occupancy of H3K27me3 was reduced while H3K27 demethylase KDM6A was enriched on genomes of KO cells. Integration with gene expression data revealed significant correlations with histone and KDM6A ChIPseq, identifying them as a main driver of Kmt2c or Kmt2d KO-specific gene regulation. Although our datasets revealed more unique than shared signatures, we found Mmp3 being a common target upon Kmt2c or Kmt2d KO. Indeed, downregulation of Mmp3 reversed induction of Kmt2c and Kmt2d KO-dependent brain metastases. Finally, we found that Kdm6a knockdown reduces Mmp3 levels, again, leading to reduction of brain metastases of Kmt2c or Kmt2d KO cells.
2024-05-07 | MSV000094701 | MassIVE
Project description:Chronic injury and inflammation pose high risks for epithelial dysplasia and cancer. In the “field cancerization” model, spontaneous mutations confer a stem-cell fitness advantage and promote gradual clonal expansion. Here, through 3d imaging, fate-mapping, biophysical modeling, and single-cell transcriptomics in a mouse model of acute colitis, we define an alternate, rapid mechanism for clonal expansion: the neutral activation of metabolically reprogrammed “founder progenitor cells” (FPCs) during wound healing. FPCs leverage the breakdown of normal crypt regenerative boundaries to expand multiplicatively into new crypts patterned from a zone of cellular mixing and plasticity. FPCs represent relatively generic proliferative cells probabilistically emerging from a background of fetal-reprogrammed epithelium and derive from both surface and basal zones of the injured colonic mucosa. Acute wound healing activates spatial and lineage plasticity to generate clonal fields without significant mutational burden. These results suggest that hallmark pre-neoplastic changes may arise from a punctuated pattern of injury and healing rather than gradual field cancerization.
2023-07-14 | GSE193342 | GEO
Project description:Somatic mutations of the KMT2D methyltransferase gene represent a common genetic lesion in multiple cancer types. In diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), these mutations are highly recurrent and occur early during tumorigenesis, suggesting a central role in transformation. Here we show that FL/DLBCL-associated KMT2D mutations impair its enzymatic activity and lead to diminished global H3K4 methylation in germinal center (GC) B cells and DLBCL, consistent with the enrichment of KMT2D binding at enhancer and promoter regions marked by mono- and tri-methylation. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, leads to an increase in GC B cells, whose transcriptional profile is enriched in cell-cycle regulatory and B-cell receptor signaling genes. Consistently, Kmt2d-deficient B cells exhibit proliferative advantage ex vivo. Loss of Kmt2d combined with BCL2 deregulation, mimicking FL/DLBCL pathogenesis, leads to an increased incidence of clonal lymphoproliferations resembling the features of the human tumors. These findings suggest that early KMT2D loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may represent a rational therapeutic approach targeting early tumorigenic events.
2015-09-10 | GSE67494 | GEO
Project description:Inactivating mutations of the KMT2D methyltransferase and the CREBBP acetyltransferase are among the most common genetic alterations in B-cell lymphoma and co-occur in 40-60% of follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) cases, suggesting they may be co-selected. Here we show that combined germinal center (GC)-specific haploinsufficiency of Crebbp and Kmt2d synergize in vivo to promote the expansion of abnormal GCs, a common pre-neoplastic event. These enzymes form a biochemical complex on selected enhancers/super-enhancers that are critical for the delivery of signals in the GC light-zone and are only corrupted upon dual Crebbp/Kmt2d loss, both in mouse GC B cells and in human DLBCLs. Moreover, we find that CREBBP directly acetylates KMT2D in GC-derived B cells. Accordingly, inactivation of CREBBP by FL/DLBCL-associated truncating and/or missense mutations abrogates its ability to catalyze KMT2D acetylation. Importantly, genetic and pharmacologic loss of CREBBP and the consequent decrease in KMT2D acetylation leads to reduced levels of H3K4me1, supporting a role for acetylation in modulating KMT2D activity. These data identify a direct biochemical and functional interaction between CREBBP and KMT2D, with implications for their role as tumor suppressors in FL/DLBCL and for the development of combinatorial therapies targeting enhancer defects induced by their loss.
2023-02-28 | GSE220255 | GEO
Project description:Follicular lymphoma (FL) is the most common indolent type of B-cell non-Hodgkin lymphoma. Advances in treatment have improved overall survival, but early relapse or transformation to aggressive disease is associated with inferior outcome. To identify early genetic events and track tumor clonal evolution, we performed multi-omics analysis of 94 longitudinal biopsies from 44 FL patients; 22 with transformation (tFL) and 22 with relapse without transformation (nFL). Deep whole-exome sequencing confirmed recurrent mutations in genes encoding epigenetic regulators (CREBBP, KMT2D, EZH2, EP300), with similar mutational landscape in nFL and tFL patients. Calculation of genomic distances between longitudinal samples revealed complex evolutionary patterns in both subgroups. CREBBP and KMT2D mutations were identified as genetic events that occur early in the disease course, and cases with CREBBP KAT domain mutations had low risk of transformation. Gains in chromosomes 12 and 18 (TCF4), and loss in 6q were identified as early and stable copy number alterations. Identification of such early and stable genetic events may provide opportunities for early disease detection and disease monitoring. Integrative analysis revealed that tumors with EZH2 mutations exhibited reduced gene expression of numerous histone genes, including histone linker genes. This might contribute to the epigenetic dysregulation in FL.
2024-08-20 | GSE272403 | GEO
Project description:Recurrences of diffuse large B-cell lymphomas (DLBCL) result in significant morbidity and mortality, but their underlying genetic and biological mechanisms are unclear. Clonal relationship in DLBCL relapses so far is mostly addressed by the investigation of immunoglobulin (IG) rearrangements, therefore lacking deeper insights into genome-wide lymphoma evolution. We studied mutations and copy number aberrations in 20 paired relapsing and 20 non-relapsing DLBCL cases aiming to test the clonal relationship between primaries and relapses, to track tumorsâ genetic evolution and to investigate the genetic background of DLBCL recurrence. Three clonally-unrelated DLBCL relapses were identified (15%). Also, two distinct patterns of genetic evolution in clonally-related relapses were detected: (1) early-divergent/branching evolution from a common progenitor in 6 patients (30%), and (2) late-divergent/linear progression of relapses in 11 patients (65%). Analysis of recurrent genetic events identified potential early drivers of lymphomagenesis (KMT2D, MYD88, CD79B and PIM1). The most frequent relapse-specific events were additional mutations in KMT2D and alterations of MEF2B. SOCS1 mutations were exclusive to non-relapsing DLBCL, whereas primaries of relapsing DLBCL more commonly displayed gains of 10p15.3-p12.1 containing the potential oncogenes PRKCQ, GATA3, MLLT10 and ABI1. Altogether, our study expands knowledge on clonal relationship, genetic evolution and mutational basis of DLBCL relapses. There are 62 copy number Agilent 180k SurePrint arrays in total, which represent 40 cases. There are 21 arrays of primary relapsing DLBCL tumors, 21 arrys of matched relapses and 20 arrays of non relapsing DLBCLs.
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Project description:The transcriptional coactivator Yap promotes proliferation and inhibits apoptosis, suggesting that Yap functions as an oncogene. Most oncogenes, however, require a combination of at least two signals to promote proliferation. Here we present evidence that Yap activation is insufficient to promote growth in the otherwise normal tissue. Using a mosaic mouse model, we demonstrate that Yap overexpression in a fraction of hepatocytes does not lead to their clonal expansion, as proliferation is counterbalanced by increased apoptosis. To shift the activity of Yap towards growth, a second signal provided by tissue damage or inflammation is required. In response to liver injury, Yap drives clonal expansion, suppresses hepatocyte differentiation and promotes a progenitor phenotype. These results suggest that Yap activation is insufficient to promote growth in the absence of a second signal thus coordinating tissue homeostasis and repair.
2015-02-07 | GSE65207 | GEO